3-(Bromomethyl)-1-methyl-1H-indazole → N-Isopropyl-N-(4-methoxy-phenyl)-2-[3-(1-methyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]acetamide

HRID 343217Notes

Reaction equation

HRID 343217 reaction equation
[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH2:45]Br)=[N:37]1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]([CH3:35])[N:37]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]

Participants

5

Reactant 2

HCID 107755483-(Bromomethyl)-1-methyl-1H-indazoleHCID 107900232-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide

Product 1

HCID 10555571N-Isopropyl-N-(4-methoxy-phenyl)-2-[3-(1-methyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]acetamideYield 22.8%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent2×

Procedure

To a stirring solution of 330 mg (0.73 mmol) of 2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL DMF at 0° C. is added dropwise over 5 min 1.75 mL (0.87 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 180 mg (1.18 mmol, 1.1 equiv) of 1-methyl-3-bromomethyl-1H-indazole in 3 mL DMF is added. The resulting solution is stirred 3 h at RT and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by further purification via silica gel MPLC using a Si60 column and hexane/EtOAc 1/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 100 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.74 (d, 1H, J=8.3), 7.25-6.76 (m, 16H), 4.85 (m, 1H), 4.11 (s, br, 2H), 3.97 (dd, 1H, J=5.6, 7.8), 3.77 (s, 3H), 3.70 (s, 3H), 3.63 (dd, 1H, J=7.8, 15.9), 3.48 (dd, 1H, J=5.6, 15.9), 0.92 (d, 6H, J=6.8); low resolution MS (FAB)m/e 602 (MH+), 437. Anal. (C36H35N5O4) Calcd. C, 71.86; H, 5.86; N, 11.64; Found C, 71.69; H, 5.91; N, 11.56.

Workup

  1. stirringThe resulting solution is stirred 3 h at RT
  2. customquenched with 5 mL of H2O
  3. additionThe reaction mixture is poured into 50 mL of EtOAc
  4. extractionextracted with H2O (2×50 mL)
  5. customThe organic layer is separated
  6. dry with materialdried (MgSO4)
  7. customthe solvents removed in vacuo
  8. customPurification by silica gel flash column chromatography
  9. customfollowed by further purification via silica gel MPLC

Sources & evidence

ORD record
ord-4962be34ea9640d38fe5723588cb21b3
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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